A class of amphiphilic photosensitizers for photodynamic therapy (PDT) was developed. Sulfonate esters of modified porphyrins bearing-F substituents in the
positions of the phenyl rings have adequate ...properties for PDT, including absorption in the red, increased cellular uptake, favorable intracellular localization, low cytotoxicity, and high phototoxicity against A549 (human lung adenocarcinoma) and CT26 (murine colon carcinoma) cells. Moreover, the role of type I and type II photochemical processes was assessed by fluorescent probes specific for various reactive oxygen species (ROS). The photodynamic effect is improved not only by enhanced cellular uptake but also by the high generation of both singlet oxygen and oxygen-centered radicals. All of the presented results support the idea that the rational design of photosensitizers for PDT can be further improved by better understanding the determinants affecting its therapeutic efficiency and explain how smart structural modifications can make them suitable photosensitizers for application in PDT.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Manganese porphyrins have several therapeutic/imaging applications, including their use as radioprotectants (in clinical trials) and as paramagnetic MRI contrast agents. The affinity of porphyrins ...for lipid bilayers also makes them candidates for cell/liposome labelling. We hypothesised that metalation with the positron emission tomography (PET) radionuclide 52Mn (t1/2 = 5.6 d) would allow long-term in vivo biodistribution studies of Mn-porphyrins, as well as a method to label and track cells/liposomes, but methods for fast and efficient radiolabelling are lacking.
Several porphyrins were produced and radiolabelled by addition to neutralised 52MnMnCl2 and heating using a microwave (MW) synthesiser, and compared with non-MW heating. MW radiosynthesis allowed >95 % radiochemical yields (RCY) in just 1 h. Conversely, non-MW heating at 70 °C for 1 h resulted in low RCY (0–25 % RCY) and most porphyrins did not reach radiolabelling completion after 24 h. Formation of the 52Mn-complexes were confirmed with radio-HPLC by comparison with their non-radioactive 55Mn counterparts. Following this, several 52MnMn-porphyrins were used to radiolabel liposomes resulting in 75–86 % labelling efficiency (LE). Two lead 52MnMn-porphyrins were taken forward to label MDA-MB-231 cancer cells in vitro, achieving ca. 11 % LE. After 24 h, 32–45 % of the 52MnMn-porphyrins was retained in cells.
In contrast to standard methods, MW heating allows the fast synthesis of 52MnMn-porphyrins with >95 % radiochemical yields that avoid purification. 52MnMn-porphyrins also show promising cell/liposome labelling properties. Our reported technique can potentially be exploited for the in vivo imaging of Mn-porphyrin therapeutics, as well as for the accurate in vivo quantification of Mn-porphyrin MRI agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
For the development of redox responsive MRI probes based on the MnIII/MnII couple, stable complexation of both reduced and oxidized forms of the metal ion and appropriate tuning of the redox ...potential in the biologically relevant range are key elements. The water soluble fluorinated Mn-porphyrin derivative Mn-3 satisfies both requirements. In aqueous solutions, it can reversibly switch between MnIII/MnII oxidation states. In the presence of ascorbic acid or β-mercaptoethanol, the MnIII form undergoes reduction, which is slowly but fully reversed in the presence of air oxygen. A UV-Vis kinetic study of MnIII/MnII reduction under oxygen-free conditions yielded second-order rate constants, k2, of 46.1 M-1 s-1 and 13.8 M-1 s-1 for the reaction with ascorbic acid and β-mercaptoethanol, respectively. This could correspond, in the absence of oxygen, to a half-life of a few minutes in blood plasma and a few seconds in circulating immune cells where ascorbic acid reaches 20-40 μM and a few mM concentrations, respectively. In contrast to expectations based on the redox potential, reduction with glutathione or cysteine does not occur. It is prevented by the coordination of the glutathione carboxylate group(s) to MnIII in the axial position, as was evidenced by NMR data. Therefore, MnIII-3 acts as an ascorbate specific turn-on MRI probe, which in turn can be re-oxidized by oxygen. The relaxivity increase from the oxidized to the reduced form is considerably improved at medium frequencies (up to 80 MHz) with respect to the previously studied Mn-TPPS4 analogues; at 20 MHz, it amounts to 150%. No in vitro cytotoxicity is detectable for Mn-3 in the typical MRI concentration range. Finally, 19F NMR resonances of MnIII-3 are relatively sharp which could open further opportunities to exploit such complexes as paramagnetic 19F NMR probes.
Diamagnetic metal complexes of phthalocyanines with n-butoxyl groups in all the α-benzo positions of the macrocycle skeleton, MPc(OBu)8, have strong near-infrared absorptions and intense ...fluorescences that are Stokes shifted by more than 15 nm. Interestingly, the silicon complex 6 is also remarkably photostable and nontoxic. The use of 6 in the fluorescence imaging of BALB/c mice bearing a 4T1-luc2 tumor in the mammary fat pad unambiguously revealed the presence of the tumor when it was only 1 mm in diameter and was not visible with the naked eye. Compound 6 has an intrinsic ability to accumulate in the tumor, adequate spectroscopic properties, and excellent stability to function as a NIR fluorescent label in the early detection of tumors.
Materials that convert the energy of a laser pulse into heat can generate a photoacoustic wave through thermoelastic expansion with characteristics suitable for improved sensing, imaging, or ...biological membrane permeation. The present work involves the production and characterization of materials composed of an ultrathin layer of titanium dioxide (<5 μm), where a strong absorber molecule capable of very efficiently converting light into heat (5,10,15,20-tetrakis(4-sulfonylphenyl)porphyrin manganese(
iii
) acetate) is adsorbed. The influence of the thickness of the TiO
2
layer and the duration of the laser pulse on the generation of photoacoustic waves was studied. Strong absorption in a thin layer enables bandwidths of ∼130 MHz at −6 dB with nanosecond pulse laser excitation. Bandwidths of ∼150 MHz at −6 dB were measured with picosecond pulse laser excitation. Absolute pressures reaching 0.9 MPa under very low energy fluences of 10 mJ cm
−2
enabled steep stress gradients of 0.19 MPa ns
−1
. A wide bandwidth is achieved and upper high-frequency limits of ∼170 MHz (at −6 dB) are reached by combining short laser pulses and ultrathin absorbing layers.
Strong absorption in a thin nanostructured layer enables photoacoustic generation of wide ultrasound bandwidths with nanosecond/picosecond lasers, improving imaging, sensing, or interaction with biological membranes.
Water, under microwave irradiation and at a temperature of 473 K, reaches pressures above 16 bar, being capable to act as catalyst, without the use of organic solvents and oxidants, for ...meso‐substituted porphyrin synthesis. Sustainability of the reaction is proved by E Factor=35 and EcoScale value of 50.5, the highest so far obtained for porphyrin synthesis. Methodology’s wide versatility is clearly demonstrated by the good yields obtained for both aryl and alkyl substituted porphyrins. These reaction conditions represent a huge development, not only by using very high concentrations, minimizing organic solvent usage, but also by eradicating toxic expensive solvents and oxidants.
Micro‐Porph′in‐Power Rangers: Water, under microwave irradiation and at high temperatures, aids the synthesis of meso‐substituted porphyrins. By using very high concentrations, the use of solvent can be minimized, and the solvents that are used are less toxic. Also, expensive oxidants are avoided. The sustainability merits of the reaction are evident from its E Factor of 35; the lowest obtained for porphyrin synthesis thus far.
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In the present study, we developed a green epoxidation approach for the synthesis of the diastereomers of (-)-isopulegol benzyl ether epoxide using molecular oxygen as the oxidant and a hybrid ...manganese(III)-porphyrin magnetic reusable nanocomposite as the catalyst. High activity, selectivity, and stability were obtained, with up to four recycling cycles without the loss of activity and selectivity for epoxide. The anticancer effect of the newly synthesized isopulegol epoxide diastereomers was evaluated on a human osteosarcoma cell line (MG-63); both diastereomers showed similar in vitro potency. The measured IC
values were significantly lower than those reported for other monoterpene analogues, rendering these epoxide isomers as promising anti-tumor agents against low prognosis osteosarcoma.
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Abstract
A new fluorinated manganese porphyrin, (Mn‐TPP‐
p
‐CF
3
) is reported capable of providing, based on the Mn(III)/Mn(II) equilibrium, dual
1
H relaxivity and
19
F NMR response to redox ...changes. The physical‐chemical characterization of both redox states in DMSO‐
d
6
/H
2
O evidenced that the
1
H relaxometric and
19
F NMR properties are appropriate for differential redox MRI detection. The Mn(III)‐F distance (d
Mn−F
=9.7–10 Å), as assessed by DFT calculations, is well tailored to allow for adequate paramagnetic effect of Mn(III) on
19
F
T
1
and
T
2
relaxation times. Mn‐TPP‐
p
‐CF
3
has a reversible Mn(II)/Mn(III) redox potential of 0.574 V vs. NHE in deoxygenated aqueous HEPES/ THF solution. The reduction of Mn(III)‐TPP‐
p
‐CF
3
in the presence of ascorbic acid is slowly, but fully reversed in the presence of air oxygen, as monitored by UV‐Vis spectrometry and
19
F NMR. The broad
1
H and
19
F NMR signals of Mn(III)‐TPP‐
p
‐CF
3
disappear in the presence of 1 equivalent ascorbate replaced by a shifted and broadened
19
F NMR signal from Mn(II)‐TPP‐
p
‐CF
3
. Phantom
19
F MR images in DMSO show a MRI signal intensity decrease upon reduction of Mn(III)‐TPP‐
p
‐CF
3
, retrieved upon complete reoxidation in air within ~24 h.
1
H NMRD curves of the Mn(III)/(II)‐TPP‐
p
‐CF
3
chelates in mixed DMSO/water solvent have the typical shape of Mn(II)/Mn(III) porphyrins.
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Centrosome abnormalities are a typical hallmark of human cancers. However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in ...Barrett's esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the premalignant condition to the metastatic disease. This human cancer model allows the study of sequential steps of progression within the same patient and has representative cell lines from all stages of disease. Remarkably, centrosome amplification was detected as early as the premalignant condition and was significantly expanded in dysplasia. It was then present throughout malignant transformation both in adenocarcinoma and metastasis. The early expansion of centrosome amplification correlated with and was dependent on loss of function of the tumor suppressor p53 both through loss of wild-type expression and hotspot mutations. Our work shows that centrosome amplification in human tumorigenesis can occur before transformation, being repressed by p53. These findings suggest centrosome amplification in humans can contribute to tumor initiation and progression.
Near infrared (NIR) photons are ideally suited for photomedicine because they are relatively harmless and penetrate deeply in biological tissues. However, their use is impaired by lack of ...straightforward methods to synthesize large quantities of stable infrared-absorbing molecules with long-lived excited states. Here we present a one-step synthesis of amphiphilic meso-phenyl halogenated bacteriochlorins, via hydrazide reduction, possessing strong absorption about 750 nm. The reaction proceeds efficiently, in large quantities, with a solid–solid solvent-free methodology, that is characterized by its simplicity, efficiency and minimum environmental impact. The new bacteriochlorins have unprecedented chemical and photophysical properties, namely strong electronic absorption above 720 nm, adequate photostability, low fluorescence quantum yield and n-octanol/water partition coefficients (log POW) ranging from −1.7 to >4, meaning that the library of compounds synthesized in this work is versatile enough to be applied in photodynamic therapy for a range of biological targets.
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